Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death

Abstract

The present invention relates to compounds which are inhibitors of non-apoptotic regulated cell death, and to pharmaceutical compositions containing such compounds. Furthermore, the present invention relates to the use of such compounds and pharmaceutical compositions in therapy, in particular in the treatment of a condition, disorder or disease that is characterized by non-apoptotic regulated cell-death or where non-apoptotic regulated cell-death is likely to play or plays a substantial role. The compounds and pharmaceutical compositions described herein are also useful in the treatment of a condition, disorder or disease that is characterized by oxidative stress or where oxidative stress is likely to play or plays a substantial role; and/or a condition, disorder or disease that is characterized by activation of (1) one or more components of the necrosome; (2) death domain receptors; and/or (3) Toll-like receptors; and/or (4) players in ferroptotic/ferroptosis signalling, or where activation of any one of (1) to (3) and/or (4) is likely to play or plays a substantial role.

The invention claimed is: 
     
       1. A method for treating a condition, disorder or disease in a subject in need thereof, the method comprising administering to the subject a compound selected from the group consisting of a spiroquinoxaline derivative having the general formula (I) 
       
         
           
           
               
               
           
         
         and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labeled forms, prodrugs, and combinations thereof, 
         wherein 
         E is —N(R 6 )—; 
         L is selected from the group consisting of C 1-10  alkylene, C 2-10  alkenylene, C 2-10  alkynylene, 1,1-(CH 2 ) a -cyclopropylene-(CH 2 ) b —, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH 2 ) m —[Y—(CH 2 ) n ] o —, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1; Y is independently selected from O, S, and —N(R 7 )—; and each of the C 1-10  alkylene, C 2-10  alkenylene, C 2-10  alkynylene, 1,1-cyclopropylene, —(CH 2 ) m —, and —(CH 2 ) n — groups is optionally substituted with one or more independently selected R 30 ; 
         G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R 8 ; 
         ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene, a monocyclic 4- to 10-membered O/S-heterocycloalkylene, or a monocyclic 3- to 10-membered cycloalkylene, wherein each of the N-heterocycloalkylene, O/S-heterocycloalkylene, and cycloalkylene groups is optionally substituted with one or more independently selected R 9 ; 
         R 1  is H; 
         R 2 , R 3 , R 4 , and R 5  are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —N(R 11 )(OR 11 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         or R 2  and R 3  may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ; R 3  and R 4  may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ; and/or R 4  and R 5  may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ; 
         R 6  is H; 
         R 7  is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR 11 , and —NHR 20 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         R 8  is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —N(R 11 )(OR 11 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         R 9  is, when substituting a hydrogen atom bound to a ring carbon atom, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 12 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 , and/or any two R 9  which are bound to the same carbon atom of ring A may join together to form ═X; or 
         R 9  is, when substituting a hydrogen atom bound to a ring nitrogen atom, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR 11 , —N(R 12 )(R 13 ), —S(O) 1-2 R 11 , —S(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —N(R 14 )C(═X)R 11 , and —N(R 14 )C(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; or R 9  is, when bound to a ring sulfur atom of ring A, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR 11 , and ═O, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         X is independently selected from O, S, and N(R 14 ); 
         R 11  is, in each case, selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         R 12  and R 13  are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 12  and R 13  may join together with the nitrogen atom to which they are attached to form the group —N═CR 15 R 16 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         R 14  is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         R 15  and R 16  are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NH y R 20   2-y , or R 15  and R 16  may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; 
         y is an integer from 0 to 2; 
         R 20  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; and 
         R 30  is a 1 st  level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 71 , —N(R 72 )(R 73 ), —S(O) 0-2 R 71 , —S(O) 1-2 OR 71 , —OS(O) 1-2 R 71 , —OS(O) 1-2 OR 71 , —S(O) 1-2 N(R 72 )(R 73 ), —OS(O) 1-2 N(R 72 )(R 73 ), —N(R 71 )S(O) 1-2 R 71 , —NR 71 S(O) 1-2 OR 71 , —NR 71 S(O) 1-2 N(R 72 )(R 73 ), —C(═X 1 )R 71 , —C(═X 1 )X 1 R 71 , —X 1 C(═X 1 )R 71 , and —X 1 C(═X 1 )X 1 R 71 , and/or any two R 30  which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X 1 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1 st  level substituent is optionally substituted by one or more 2 nd  level substituents, wherein said 2 nd  level substituent is, in each case, independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF 3 , —CN, azido, —NO 2 , —OR 81 , —N(R 82 )(R 83 ), —S(O) 0-2 R 81 , —S(O) 1-2 OR 81 , —OS(O) 1-2 R 81 , —OS(O) 1-2 OR 81 , —S(O) 1-2 N(R 82 )(R 83 ), —OS(O) 1-2 N(R 82 )(R 83 ), —N(R 81 )S(O) 1-2 R 81 , —NR 81 S(O) 1-2 OR 81 , —NR 81 S(O) 1-2 N(R 82 )(R 83 ), —C(═X 2 )R 81 , —C(═X 2 )X 2 R 81 , —X 2 C(═X 2 )R 81 , and —X 2 C(═X 2 )X 2 R 81 , and/or any two 2 nd  level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1 st  level substituent may join together to form ═X 2 , wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2 nd  level substituent is optionally substituted with one or more 3 rd  level substituents, wherein said 3 rd  level substituent is, in each case, independently selected from the group consisting of C 1-3  alkyl, halogen, —CF 3 , —CN, azido, —NO 2 , —OH, —O(C 1-3  alkyl), —OCF 3 , —S(C 1-3  alkyl), —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —NHS(O) 2 (C 1-3  alkyl), —S(O) 2 NH 2-z (C 1-3  alkyl) z , —C(═O)OH, —C(═O)O(C 1-3  alkyl), —C(═O)NH 2-z (C 1-3  alkyl) z , —NHC(═O)(C 1-3  alkyl), —NHC(═NH)NH z-2 (C 1-3  alkyl) z , and —N(C 1-3  alkyl)C(═NH)NH 2-z (C 1-3  alkyl) z , wherein z is 0, 1, or 2 and C 1-3  alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3 rd  level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2 nd  level substituent may join together to form ═O, ═S, ═NH, or ═N(C 1-3  alkyl); 
         wherein 
         R 71 , R 72 , and R 73  are independently selected from the group consisting of —H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C 1-3  alkyl, halogen, —CF 3 , —CN, azido, —NO 2 , —OH, —O(C 1-3  alkyl), —OCF 3 , ═O, —S(C 1-3  alkyl), —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —NHS(O) 2 (C 1-3  alkyl), —S(O) 2 NH 2-z (C 1-3  alkyl) z , —C(═O)(C 1-3  alkyl), —C(═O)OH, —C(═O)O(C 1-3  alkyl), —C(═O)NH 2-z (C 1-3  alkyl) z , —NHC(═O)(C 1-3  alkyl), —NHC(═NH)NH z-2 (C 1-3  alkyl) z , and —N(C 1-3  alkyl)C(═NH)NH 2-z (C 1-3  alkyl) z , wherein z is 0, 1, or 2 and C 1-3  alkyl is methyl, ethyl, propyl or isopropyl; 
         R 81 , R 82 , and R 83  are independently selected from the group consisting of —H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C 1-3  alkyl, halogen, —CF 3 , —CN, azido, —NO 2 , —OH, —O(C 1-3  alkyl), —OCF 3 , ═O, —S(C 1-3  alkyl), —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —NHS(O) 2 (C 1-3  alkyl), —S(O) 2 NH 2-z (C 1-3  alkyl) z , —C(═O)(C 1-3  alkyl), —C(═O)OH, —C(═O)O(C 1-3  alkyl), —C(═O)NH 2-z (C 1-3  alkyl) z , —NHC(═O)(C 1-3  alkyl), —NHC(═NH)NH z-2 (C 1-3  alkyl) z , and —N(C 1-3  alkyl)C(═NH)NH 2-z (C 1-3  alkyl) z , wherein z is 0, 1, or 2 and C 1-3  alkyl is methyl, ethyl, propyl or isopropyl; and 
         X 1  and X 2  are independently selected from O, S, and N(R 84 ), wherein R 84  is —H or C 1-3  alkyl, 
         wherein the condition, disorder or disease is: 
         (ii) a condition, disorder or disease where oxidative stress caused by glutathione depletion plays a role; 
         (iv) a condition, disorder or disease selected from the group consisting of a neurodegenerative disease of the central or peripheral nervous system, muscle wasting, muscular dystrophy, ischemia, compartment syndrome, gangrene, pressure sores, sepsis, degenerative arthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic disease, avascular necrosis, diabetes, sickle cell disease, alteration of blood vessels, cancer-chemo/radiation therapy-induced cell-death and intoxication, paracetamol (APAP) intoxication, cisplatin intoxication, traumatic brain injury, rheumatoid arthritis, multiple sclerosis, lipopolysaccharide (LPS)-induced endotoxic shock, ischemia reperfusion injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), dementia or is the result of, arises from or is associated with any of the foregoing; and/or 
         (v) a condition, disorder or disease which is the result of, arises from or is associated with a circumstance selected from the group consisting of forms of infection of viruses, or fungi; a reduction in cell-proliferation, an alteration in cell-differentiation or intracellular signalling; an undesirable inflammation; cell death of retinal neuronal cells, cardiac muscle cells, or cells of the immune system or cell death associated with renal failure; neonatal respiratory distress, asphyxia, incarcerated hernia, placental infarct, iron-load complications, endometriosis, congenital disease; head trauma/traumatic brain injury, liver injury; injuries from environmental radiation; burns; cold injuries; mechanical injuries, and decompression sickness. 
       
     
     
       2. The method of  claim 1 , wherein ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene. 
     
     
       3. The method of  claim 1 , wherein when R 2  to R 5  are each H, L is —CH 2 —, and
 (i) G is unsubstituted phenyl, then ring A is not 
 
       
         
           
           
               
               
           
         
       
       wherein R 9  is —S(O) 2 N(CH 3 ) 2 , (cyclopropyl)sulfonyl, or (3-pyridinyl)sulfonyl, or R 9  is —C(O)Z, wherein Z is methyl, tert-butyl, methoxymethyl, 2-methoxyethyl, —CH 2 NHC(O)CH 3 , 2-methoxyethylamino, morpholin-4-ylmethyl, 2-furanylmethylamino, (2-methyl-1H-imidazol-1-yl)methyl, 2-furanyl, 3-furanyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1-ethyl-1H-pyrazol-3-yl, or 1-ethyl-1H-pyrazol-5-yl;
 (ii) G is unsubstituted phenyl, then ring A is not 
 
       
         
           
           
               
               
           
         
       
       wherein R 9  is (1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl or —C(O)Z, wherein Z is 2-methoxyethylamino, methoxycarbonylmethylamino, (2-trifluoromethylphenyl)amino, 5-chloro-1H-indol-2-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, or 3-(2-thienyl)-1H-pyrazol-5-yl;
 (iii) G is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, then ring A is not 
 
       
         
           
           
               
               
           
         
         (iv) G is 3-methoxyphenyl, then ring A is not 
       
       
         
           
           
               
               
           
         
       
       wherein R 9  is (3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl;
 (v) G is 4-fluorophenyl, then ring A is not 
 
       
         
           
           
               
               
           
         
       
       wherein R 9  is —C(O)Z, wherein Z is 6-methoxy-1H-indol-2-yl or 3,4-dimethoxyphenyl; or
 (vi) G is 4-chlorophenyl, then ring A is not 
 
       
         
           
           
               
               
           
         
       
       wherein R 9  is —C(O)Z, wherein Z is 1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl. 
     
     
       4. The method of  claim 1 , wherein ring A is saturated. 
     
     
       5. The method of  claim 1 , wherein ring A contains 1 ring nitrogen atom and is 4- to 8-membered or contains 2 or 3 ring nitrogen atoms and is 5- to 8-membered, preferably ring A is 5-, 6- or 7-membered, more preferably 6- or 7-membered. 
     
     
       6. The method  claim 1 , wherein ring A is selected from the group consisting of piperidinylene, azepanylene (e.g., homopiperidinylene), azetidinylene, pyrrolidinylene, azocanylene, pyrazolidinylene, hexahydropyridazinylene, hexahydropyrimidinylene, diazepanylene (e.g., homopiperazinylene), diazocanylene, triazepanylene, and triazocanylene, each of which is optionally substituted with one or more independently selected R 9 . 
     
     
       7. The method of  claim 1 , wherein ring A is a monocyclic 4- to 10-membered O/S-heterocycloalkylene. 
     
     
       8. The method of  claim 1 , wherein when ring A is 
       
         
           
           
               
               
           
         
       
       R 2  and R 5  are both H, L is —CH 2 —, and
 (i) R 3  and R 4  are both H, then G is not 3-methylphenyl, 3-methoxyphenyl, 4-chlorophenyl, or 4-fluorophenyl; or 
 (ii) R 3  and R 4  are both methyl, then G is not 4-fluorophenyl. 
 
     
     
       9. The method of  claim 1 , wherein ring A is saturated. 
     
     
       10. The method of  claim 1 , wherein ring A contains 1 ring oxygen or sulfur atom and is 4- to 8-membered or contains 2 ring heteroatoms selected from oxygen and sulfur and is 5- to 8-membered, preferably ring A is 5-, 6- or 7-membered, more preferably 6- or 7-membered. 
     
     
       11. The method of  claim 1 , wherein ring A is selected from the group consisting of di- and tetrahydropyranylene, di- and tetrahydrothiopyranylene, oxepanylene, thiepanylene, oxetanylene, thietanylene, di- and tetrahydrofuranylene, di- and tetrahydrothienylene, oxocanylene, thiocanylene, dithiolanylene, oxathiolanylene, dioxanylene, dithianylene, oxathianylene, dioxepanylene, dithiepanylene, oxathiepanylene, dioxocanylene, dithiocanylene, and oxathiocanylene, each of which is optionally substituted with one or more independently selected R 9 . 
     
     
       12. The method of  claim 1 , wherein ring A is a monocyclic 3- to 10-membered cycloalkylene. 
     
     
       13. The method of  claim 1 , wherein when R 2  and R 5  are both H, L is —CH 2 —, and
 (i) R 3  and R 4  are both H, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not unsubstituted phenyl, 4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl;
 (ii) R 3  and R 4  are both H, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not 4-methylphenyl, 4-fluorophenyl, 3,5-difluorophenyl, or 3-methoxyphenyl;
 (iii) R 3  and R 4  are both H, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not unsubstituted phenyl, 3-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl, 3,5-difluorophenyl, or 4-trifluoromethylphenyl;
 (iv) R 3  and R 4  are both H, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not 3-methoxyphenyl;
 (v) R 3  and R 4  are both H, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3,5-difluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, or 4-trifluoromethylphenyl;
 (vi) R 3  and R 4  are both methyl, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not 3-fluorophenyl or 3,5-difluorophenyl;
 (vii) R 3  and R 4  are both methyl, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not 3-fluorophenyl or 3-methoxyphenyl; or
 (viii) R 3  and R 4  are both methyl, and ring A is 
 
       
         
           
           
               
               
           
         
       
       then G is not unsubstituted phenyl, 2-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, or 3-methoxyphenyl. 
     
     
       14. The method of  claim 1 , wherein ring A is saturated. 
     
     
       15. The method of  claim 1 , wherein ring A is 3- to 8-membered, preferably 4-, 5-, 6- or 7-membered, more preferably 6- or 7-membered. 
     
     
       16. The method of  claim 1 , wherein ring A is selected from the group consisting of cyclohexylene, cycloheptylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene, cyclohexenylene, cycloheptenylene, cyclopentenylene, and cyclooctenylene, each of which is optionally substituted with one or more independently selected R 9 . 
     
     
       17. The method of  claim 1 , wherein the condition, disorder or disease is selected from the group consisting of: paracetamol (APAP) intoxication, cisplatin intoxication, traumatic brain injury, rheumatoid arthritis, multiple sclerosis, lipopolysaccharide (LPS)-induced endotoxic shock, ischemia reperfusion injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and dementia.